DESCRIPTION (Verbatim from the Applicant's Abstract): The correct wiring together of the nervous system requires that axons extend over relatively long distances within the developing embryo and connect to very specific targets. The guidance of extending axons is controlled by the distribution of a variety of attractants and repellents in the environment through which they grow. The identification of these guidance cues will help us understand how correct wiring is achieved, and perhaps how it can be reestablished after being damaged later in life. The semaphorins are a family of signaling molecules with at least 10-15 members in any given higher vertebrate. One member of the family, chick collapsin-1 (mouse sema-D, human sema-III) is a powerful repellent of sensory neurons in vitro. When this gene is mutated in the mouse, peripheral sensory axon tracts are grossly defasciculated and enter into regions they would normally avoid. The functions of most other vertebrate semaphorins are unknown. We have made a detailed examination of the distributions of sema-E and sema-H in the embryonic chick. We then compared their expression patterns to the trajectories of axon tracts that have receptors for these two signaling molecules. A preliminary comparison has been made in embryonic mice. These descriptive studies suggest that sema-E and sema-H could act as axonal guidance cues during development. This is further supported by findings that sema-E repels sympathetic axons and attracts cortical axons in in vitro assays. Our objective is to test whether sema-E or sema-H act as axonal guidance cues during development. This will be accomplished by determining whether mutating either of these two genes by homologous recombination in mice perturbs the trajectories of extending axons in vivo.